As much as 80% of the entire world population is infected with Epstein-Barr virus, a human herpesvirus. This virus is the known causative agent of self-limiting infectious mononucleosis, and is involved in the development of two well-described forms of cancer, Burkitt's lymphoma of B cell origin, and anaplastic nasopharyngeal carcinoma. EBV is also associated with polyclonal B-cell lymphomas, lymphocytic interstitial pneumonitis and hairy leukoplakia of the tongue in AIDS patients.
EBV usually enters the body via the oropharynx, where the virus replicates in epithelial cells. It is not yet clear whether the virus then becomes truly latent or if a chronic productive infection persists. It is known that in some cases the virus does not destroy the epithelial cells which it infects. Rather, the viral genome becomes fixed in the cell as an episome and the virus becomes latent, with the episome later reappearing in nasopharyngeal carcinoma. Replication in epithelial cells is thought to provide a source of virus which infects a particular class of B lymphoid cells.
EBV can be demonstrated in the B lymphocytes of nearly all EBV-seropositive individuals. The virus persists in a latent state in these lymphocytes, with expression of the viral genome thought to be limited to the EBNA-1 gene. Primary infection can be symptomatic, such as infectious mononucleosis, or silent. The virus then usually persists for the remainder of the life of the host. Reactivations, either symptomatic or silent, detectable by increases in antibody titer to viral antigens or increases in viral replication in the saliva, can occur, though the stimuli responsible are not well characterized.
While both acyclovir and azidothymidine (AZT) suppress active EBV replication, no efficacious treatment has been found for latent herpesvirus infection, including EBV. None of the inhibitors, nucleoside analogs, pyrophosphate analogs, ribonucleotide reductase inhibitors or interferons examined have shown any effect on EBV episomal number or latent infection with any of the herpesviruses.
New therapeutic strategies are greatly desired. It is particularly desired to provide compositions and methods for therapy of EBV infections which are highly effective and at the same time possess no or only minor side effects. The provision of antisense oligonucleotide therapies for latent EBV infections in accordance with this invention satisfies a long-felt need for such therapies.